Lung Diseases and Detoxification Quiz

Metabolism and Bioactivation of Toxins in Pulmonary Tissue; α1-Antitrypsin Deficiency Syndrome

• Alpha-1 antitrypsin protects lungs from proteases.
• The liver releases alpha-1 antitrypsin into the blood.
• Deficiency of alpha-1 antitrypsin leads to lung tissue damage.
• Build-up of abnormal alpha-1 antitrypsin in the liver leads to liver cirrhosis.

Biotransformation in Lungs

• Lungs metabolize foreign compounds.
• Biotransformation modifies xenobiotics for easier elimination.
• The goal is to remove lipophilic substances that would accumulate in cell lipids.
• This process is achieved by enzymes capable of introducing new functional groups (Phase I reactions) or conjugating them with internal molecules to enhance water solubility (Phase II reactions).

Xenobiotic-Metabolizing Enzymes in Human Lung

• Phase I reactions involve oxidation reactions catalyzed by cytochrome P450-dependent monooxygenases and flavin monooxygenases, and reductions catalyzed by P450 reductase.
• Phase II reactions are catalyzed by GST (glutathione-S-transferase), UDP-glucuronyltransferase, epoxide hydrolase, sulphotransferase, and N-acetyltransferase.

Scheme of Xenobiotic Detoxification

• Phase I reactions convert xenobiotics into reactive electrophiles.
• Phase II reactions detoxify the reactive electrophiles, making them more hydrophilic.
• Reacts with proteins and DNA
• These metabolites may be cleaved by enzymes in the kidney and colon to produce mutagens and carcinogens.
• The final products are excreted.

Metabolic Bioactivation

• Biotransformation of foreign compounds can be beneficial for eliminating them.
• However, it can also activate harmless substances into reactive forms, such as the metabolic activation of benzo(a)pyrene for binding to DNA and leading to cancer.
• CYP450 enzymes are involved in the activation and subsequent detoxification of benzo[a]pyrene (B[a]P).

Expression of P450 Enzymes in Pulmonary Tissue

• P450 monooxygenases are responsible for the oxidative metabolism of xenobiotics, drugs, environmental pollutants, and carcinogens.
• P450 enzymes utilize oxygen and NADPH-cytochrome P450 to oxidize xenobiotics and generate water.
• CYP1A1, CYP1B1, CYP2B6, CYP2E1, CYP2J2, and CYP3A5 are expressed in the lung, bronchial epithelium, Clara cells, type II pneumocytes, and alveolar macrophages.

Expression of Phase II Enzymes in Pulmonary Tissue

• Phase II enzymes play a role in the elimination of metabolites.
• GSTs, UGTs, and epoxide hydrolases are present in pulmonary tissue.
• GSTs catalyze the conjugation of glutathione to a variety of endogenous and exogenous electrophilic compounds.

Diseases of the Respiratory System

• Non-infective diseases are grouped into obstructive and restrictive types.
• Obstructive diseases include emphysema, chronic bronchitis, bronchiectasis, and asthma (impaired airflow).
• Restrictive diseases involve restriction of lung expansion due to fibrosis.

What is Emphysema?

• Emphysema is characterized by loss of elastic recoil in the lungs.
• This leads to increased compliance and the inability to expel air from the lungs.
• Air gets trapped in the alveoli, which cluster together, forming blebs.
• Emphysema is a form of COPD.

Causes of COPD

• Cigarette smoking, α1-antitrypsin deficiency, hypocomplementemic urticarial vasculitis, intravenous Ritalin abuse, Ehlers-Danlos syndrome, Marfan syndrome, Salla disease, α1-antichymotrypsin deficiency, and HIV (emphysema-like illness) are possible COPD causes.

Classification of Emphysema

• Emphysema is classified into panacinar and centrilobular types.
• Panacinar emphysema involves all portions of the acinus and secondary pulmonary lobule uniformly, usually in the lower lobes.
• Centrilobular emphysema primarily affects the respiratory bronchioles, usually in the upper lobes.

Emphysema and α1-Antitrypsin

• Elastin is a lung protein and the enzyme elastase, secreted by neutrophils, breaks it down.
• α1-antitrypsin inhibits elastase to prevent the degradation of elastin and the damage seen in emphysema.
• Deficiency of α1-antitrypsin, especially in smokers, leads to the destruction of lung tissue due to loss of elastin.

Alpha-1 Antitrypsin Deficiency

• In normal conditions, alpha-1 antitrypsin protects lungs from damage by enzymes.
• In deficiency, alpha-1 antitrypsin is trapped in the liver, causing liver damage. In the lungs, neutrophil elastase is not inhibited; therefore, lung damage occurs.

Centroacinar Emphysema

• Centroacinar emphysema mainly affects the respiratory bronchioles.
• Cigarette smoke containing nicotine contributes to this type of emphysema by acting as a major attractant for neutrophils.
• Nicotine increases the activity of several pathways resulting in an increase in neutrophil activation and elastase.

Bronchitis

• Bronchitis involves inflammation of the bronchial mucus membranes.
• It can be acute or chronic.
• Acute bronchitis is usually caused by a temporary irritant like an infective agent (virus or bacteria) or an environmental irritant.
• Cough and mucus production are common symptoms.

Asthma

• Asthma is a chronic respiratory inflammatory condition characterized by intermittent, variable, and partly reversible constriction of bronchiolar smooth muscles.
• This can cause airway obstruction and result in difficulty breathing.
• Severe cases result in obstruction that is difficult to treat and wheezes become silent.
• The condition is associated with an inflammatory response and elevated immunoglobin E (IgE).

Asthma

• Asthma is associated with an inflammatory response causing the overproduction of IgE, which blocks beta-2 receptors in smooth muscles.
• The beta-adrenergic theory of asthma explains the mechanism behind this condition.

Asthma

• Genetic and other variables can make cells in the bronchi hypersensitive to environmental triggers.
• Environmental triggers stimulate an immune response (B-cell/helper T-cell (Th2) response) resulting in the production of antibodies to the trigger.
• This can cause a hypersensitivity response resulting in IgE production from plasma cells, interacting with mast and basophil cells.

Acute Respiratory Distress Syndrome (ARDS)

• ARDS is a severe lung condition defined by hypoxemia and stiff lungs.
• It occurs in response to various injuries and progresses through different phases.
• The pathology of ARDS involves an exudative, proliferative, and fibrotic phase.

Phases of ARDS

• Exudative phase: inflammation, increased vascular permeability, neutrophil influx, decreased surfactant, and impaired endothelial cells.
• Proliferative phase: decrease in type II pneumocytes, early fibrotic changes, and thickened alveolar capillaries.
• Fibrotic phase: increased collagen deposition and decreased compliance.

Lung Injuries and Symptoms

• Direct lung injuries include pneumonia, breathing in smoke, use of ventilators, and nearly drowning.
• Indirect lung injuries include sepsis, blood transfusions, severe chest injuries, severe bleeding, pancreatitis, fat embolism, and drug reactions.
• Common symptoms of lung injuries include dyspnea, tachypnea, and hypoxemia. Severe cases might lead to hypotension, confusion, and cyanosis.

Cyanosis

• Cyanosis is the bluish discoloration of the skin and mucous membranes due to low oxygen levels in the blood.
• It's caused by low oxygen levels in the red blood cells or difficulties in oxygenating the blood due to certain lung or heart conditions.

Biochemical Basis of Lung Injuries

• Inflammation is a crucial component in lung injuries, leading to increased vascular permeability, edema, neutrophil and macrophage influx, and damage to alveoli.
• Impaired oxygen exchange, increased breathing rate, and respiratory acidosis are results of the inflammatory response.
• Fibrous tissue deposition, collapse of alveoli, and decrease in compliance are caused by further inflammation and dysfunction of type II alveolar cells.

Cystic Fibrosis (CF)

• CF is an autosomal recessive multisystem disease caused by mutations in the CFTR gene.
• Chronic sino-pulmonary disease, nutritional deficiency/GI abnormality, and electrolyte abnormality are commonly observed conditions in CF.

Who is Affected by CF?

• CF affects about one in 2,500 people of European descent.
• Median survival is 25 years, and the number of patients reaching their 30s is increasing.

Autosomal Recessive Inheritance in CF

• CF is an autosomal recessive disorder.
• If both parents carry the CFTR gene mutation, there is a 25% chance of a child inheriting the disease, and a 50% chance of being a carrier.

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Gene

• The CFTR gene is located on chromosome 7; the F508 mutation is common in Caucasians.
• There are 1522 mutations identified in the CFTR mutation database.

The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)

• CFTR is a protein made of 1,480 amino acids forming a specific 3D structure.
• It's a member of the ATP-binding cassette (ABC) superfamily.
• The CFTR protein acts as an ion channel, moving chloride ions across epithelial membranes.

What Does the CFTR Protein Do?

• CFTR is an ion channel moving chloride ions from inside the cell to outside.
• These chloride ions attract a water layer that helps cilia sweep away mucus.

Disease-Causing Mutation Subclasses in Cystic Fibrosis

• There are over 1700 CFTR mutations classified into 5 categories based on pathogenic mechanisms.
• Some mutations are approved for treatment with CFTR modulators.
• Different populations have different frequencies for specific mutations.

How Do Problems With the CFTR Protein Cause CF?

• Problems with the CFTR protein lead to the trapping of chloride ions inside the cell.
• This reduces water outside the cell and causes the mucus to become dehydrated and thick, impairing ciliary function.
• Mucus buildup obstructs airways, provides a breeding ground for bacteria, and causes infections.

Airway Surface Liquid Low Volume Hypothesis

• Clearance of mucus depends on ciliary function and secretion.
• Optimal volume of airway surface liquid (ASL) facilitates bacteria entrapment.
• ASL volume is regulated by the absorption of Na+ ions and secretion of Cl- ions.
• Defects in CFTR reduce Cl- secretion, decreasing ASL volume.

Airway Surface Liquid Low Volume Hypothesis and CFTR

• Normal CFTR inhibits sodium channels (ENaC).
• This inhibition reduces sodium absorption, which has a downstream effect on ASL volume.
• In CF, mutant CFTR does not inhibit ENaC properly, increasing sodium absorption and reducing ASL volume.
• This reduced ASL volume leads to poor mucociliary clearance, accumulation of mucus, and increased bacterial infection risk.

Airway Surface Liquid Low Volume Hypothesis and Consequences

• Depleted ASL volume negatively affects ciliary function, impairing mucus clearance.
• This results in concentrated mucus that adheres to the airway surface, increasing the susceptibility to chronic infections.

CF Lung Pathophysiology

• Diminished host defenses lead to recurring bacterial infections.
• Common bacterial pathogens in CF include Pseudomonas aeruginosa, Staphylococcus aureus, Haemophilus influenzae, and Burkholderia cepacia.
• The subsequent inflammation, infection, and obstruction lead to bacterial toxins, impaired gas exchange, and chronic respiratory failure.

CF Symptoms

• Pulmonary Symptoms: cough, increased sputum production, recurrent pneumonia, and digital clubbing.
• Gastrointestinal Symptoms: pancreatic enzyme insufficiency, fat-soluble vitamin deficiency, and malnutrition.

Diagnosis-Sweat Chloride

• Sweat chloride tests are used to diagnose cystic fibrosis.
• Elevated sweat chloride levels (60-165 meq/L) indicate cystic fibrosis.

Prenatal Screening

• The American College of Obstetricians and Gynecologists recommends carrier testing for CF mutations during pregnancy.
• Testing sensitivity for CF among the white population is relatively low (~78%).
• The testing sensitivity is lower in racial and ethnic minority populations.

Cystic Fibrosis-Treatment is Multidisciplinary

• Treatment of cystic fibrosis requires a multidisciplinary approach.
• Key components include airway clearance, infection management, nutritional support, gastrointestinal care, inflammation management, and fertility counseling, as well as social support.